Project Summary/Abstract The GABAergic system of the mammalian brain consists of neurons that release GABA and receptors that bind GABA. The GABA-releasing cells are extraordinarily diverse and highly specialized. Some GABAergic cells control the activity in a local network (interneurons, INs), while others constitute the output of a well-defined structure (e.g., striatal medium spiny neurons, MSNs). The receptors for GABA are also diverse and specific. Ligand-gated GABA receptors (GABAARs), members of the Cys-loop receptor family, are present on virtually every neuron in the brain and perform different functions depending on their synaptic or extrasynaptic localization. The GABAARs located outside the synapses (peri- or extrasynaptically) are activated by GABA molecules present in the extracellular space. These GABAARs mediate a type of inhibition that is always on, also termed tonic inhibition. The studies completed during the past funding period have addressed fundamental mechanisms related to the nature, pharmacology and origin of tonic inhibition. As a direct continuation of the research carried out during the previous funding period, the present project will focus on novel and untested roles of the tonic GABA conductance in cellular/network excitability and neuroprotection. The proposal will address a specific hypothesis using state-of-the-art electrophysiological, microscopical, molecular pharmacological, optical, and transgenic mouse technologies. The hypothesis posits that a tonically active GABAAR-mediated conductance is essential for protecting highly vulnerable neurons in the brain against hyperexcitability and neurotoxicity. The aim is to focus on two damage-prone brain regions where this conductance is present, but can be altered under various conditions. The proposed studies will elucidate the mechanisms whereby the tonic GABA conductance dampens excessive synchrony in the hyperexcitable hippocampal CA3 region and how it protects neostriatal neurons against neurotoxicity. Considering the extremely excitable nature of the CA3 region and its relevance to epilepsy, and the high susceptibility of the neostriatum to dysfunction and degeneration, these experiments will address central issues related to the pathologies and treatments of epilepsies, Huntington's disease (HD), Tourettes syndrome (TS) and other disorders of the limbic system and striatum. The studies are expected to generate novel pharmacological interventions specific for tonic inhibition for the treatment of disorders related to neuronal synchrony including epilepsy and cognitive disorders, and for treating or preventing neurodegenerative conditions of the striatum and other damage-prone brain structures.